PARP1 catalytic variants reveal branching and chain length-specific functions of poly(ADP-ribose) in cellular physiology and stress response

Lisa Aberle, Annika Krüger, Julia M Reber, Michelle Lippmann, Matthias Hufnagel, Michael Schmalz, Irmela R E. A. Trussina, Sarah Schlesiger, Tabea Zubel, Karina Schütz, Andreas Marx, Andrea Hartwig, Elisa Ferrando-May, Alexander Bürkle, and Aswin Mangerich

Nucleic Acids Research, gkaa590, https://doi.org/10.1093/nar/gkaa590

Poly(ADP-ribosyl)ation regulates numerous cellular processes and contributes to several patho-physiological conditions. Poly(ADP-ribose) (PAR) molecules are heterogeneous in chain lengths and branching frequencies, but the biological significance of this is basically unknown. To check whether structural heterogeneity in PAR contributes to cell physiology and DNA damage response, the investigators transiently expressed PARP1 variants that produce PAR of different qualities and analysed select cellular and biochemical endpoints. They chose three different variants that were previously reported to synthesize either short, hyperbranched or hypobranched PAR and then performed comprehensive analyses of PAR quality in vitro and in cells, as well as of the resulting cellular consequences. They demonstrate that distinct modulations of PARP1 activity with respect to PAR branching and chain length can have significant effects on cellular physiology and intracellular molecular processes.

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